Within the family Flaviviridae, viruses belonging to the genus Hepacivirus have been shown to cause hepatitis (Hepatitis C virus (HCV) and GB virus (GBV-B)). The newly defined genus Pegivirus contains viruses similar to Hepaciviruses in genome organization but distinct in tropism and associated pathogenicity (Stapleton et al., J Gen Virol 2011: 92: 233-246). All members of the family Flaviviridae contain a positive sense, single stranded RNA genome of about 10 kb, that encodes for a single long open reading frame (ORF) polyprotein of about 3,000 amino acids (Lindenbach et al., Flaviviridae: The Viruses and Their Replication. Chapter 33. In Fields Virology Fifth Edition, (Knipe et al., Eds.) Wolters Kluwer/Lippincott Williams and Williams, Philadelphia Pa. Pages 1101-1152). The polyprotein is cleaved into smaller functional structural and nonstructural (NS) components by a combination of host and viral proteases. The viral structural proteins are encoded at the amino terminal portion of the genome and include envelope glycoproteins and a nucleocapsid. While HCV and GBV-B encode a nucleocapsid protein, HPgV-1 does not appear encode a nucleocapsid protein in the polyprotein. Phylogenetic analysis show distinct evolutionary lineages between the genera but conserved amino acid motifs involved in the enzymatic functions of the NS3 helicase and the NS5 RNA dependent RNA polymerase. The genome is organized with 5′ and 3′ untranslated regions (UTRs) that are highly conserved and that are involved both in translation and in replication of the genome.
The Pegivirus genus, is named for the persistent (pe) GB virus (g) infection that is not associated with a specific pathogenicity. In 1995-1996, the first human pegivirus, GVB-C (HPgV-1), was detected independently by two groups in sera from patients with non-A, non-B hepatitis. Although originally discovered in chronic hepatitis patients, HPgV-1 appears to be lymphotropic, and not hepatotropic, and has not been associated with hepatitis or any other clinical illness in follow-up clinical and experimental studies. Some studies, however, have suggested that co-infection with HPgV-1 may slow the progression of HIV disease (Heringlake S, J Infect Dis 1998; 177:1723-1726). Together the incidence rate of HCV and HPgV-1 is estimated to be between 2-5% of the world's population (Stapleton et al., J Gen Virol 2011: 92: 233-246).
Pegiviruses infect a wide range of mammals, not limited to chimpanzees, new world primates, bats, rodents, and horses. Recently there have been viral discovery reports indicating the novel hepaciviruses and pegiviruses have been identified in rodents and that bats may be a natural reservoir for these genera of the Flavivirdae (Quan et al., PNAS 110: 8194-8199. 2013: Drexler et al., PLoS Pathog 9 (6) e1003438. 2013: Kapoor et al., mBIo 4(2) e000216-13. 2013). The only pegiviruses previously known to infect humans is HPgV-1. There is considerable sequence divergence between pegivirus variants in the structural proteins and conservation within the nonstructural NS3 and NS5B genes (Kapoor A, mBio. 2013 March-April; 4(2): e00216-13). Sampling of bats from different continents shows several distinct bat-derived pegivirus lineages suggesting bats are a natural reservoir for pegiviruses (Quan P, Proc Natl Acad Sci USA. May 14, 2013; 110(20): 8194-8199). Characterization of HPgV-2 described in this patent shows the viral variant is distinct from the other human-tropic virus HPgV-1.
Recently, it has been proposed that Theiler's disease, the most common cause of acute hepatitis in horses, is likely to be caused by TDAV (Theiler's Disease Associated Virus), a newly described horse flavivirus, phylogenetically related to the GB viruses (Chandriana et al., PNAS 110 (15): E 1407-1415. 2013) and classified as a pegivirus. Thus, unlike the case for HPgV-1, where there has been no clear association with disease, TDAV appears to be causally related to hepatitis cases in horses.